Schizophrenia, a devastating and common disease, traditionally has been studied in early adulthood. Its course and outcome during senescence are largely unknown and subject to controversy. We have reviewed the neuropathological records of 1,046 patients who were chronically hospitalized in mental institutions. For cases who died after age 50, clinical lifetime diagnosis, as noted in the autopsy notes, was schizophrenia in 544 patients and dementia in 258 patients. The ii prevalence of neuropathological diagnoses consistent with Alzheimer's disease (AD) was 51% in the demented patients and 28% in the schizophrenics. When evaluated against age of death, AD findings in demented patients was constant, whereas the rate of such findings in schizophrenic patients rose monotonously from <5% below age 60 to 50% at age greater than or equal to 90. The age-relative rate of AD diagnosis in schizophrenic patients was markedly higher than that expected in the general population, and similar to the rate postulated in first-degree relatives of AD patients. These findings strongly suggest a hitherto-unsuspected link between aging, schizophrenia (or chronic neuroleptic treatment), and AD-like neuropathological changes. The current findings, however, are limited by the known limitations of chart diagnosis, as noted in autopsy reports. Prior to investing in a very demanding prospective study and/or a complex examination of archival historical brain tissue from neuroleptic-naive patients, we propose to confirm and extend these findings in a retrospective study, providing extensive psychiatric and normal control samples. We will identify and evaluate tissue specimens and medical charts of 600 recent schizophrenic patients. These will be compared to samples of major mood disorders (n=200) and Primary Degenerative Dementia (n=200), as well as other chronically institutionalized psychiatric patients and normal controls (n=250). We will apply blind, rigorous methods of diagnostic assessment and determine rater reliability for both neuropathological interpretation and psychiatric chart review. The results are expected to definitively detect whether chronic schizophrenia and aging are associated with increased rate of AD-like neuropathological findings in this population. This cost-effective study will then serve as the basis for a prospective determination, which will include detailed assessment of family history, and/or a similar retrospective study of tissue and records of medication-free patients.